ClinVar

Description

The L289P variant in the GDF6 gene has been reported previously in two unrelated patients with Klippel-Feil syndrome: an adult male with short neck, mirror movements, and left Sprengel anomaly, and a fetus with multiple segmentation abnormalities affecting the entire spine and ribs (Tassabehji et al., 2008). Both cases were said to be sporadic, but there is no evidence that family studies were performed. The L289P variant was not observed at any significant frequency in approximately 4500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L289P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variants in a nearby residue, E292D, has been reported in the Human Gene Mutation Database in association with Leber congenital amaurosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on review of the data in the context of the 2015 ACMG standards and guidelines for the interpretation of sequence variants (Richards et al., 2015), we now interpret L289P as a variant of uncertain significance.